Emtricitabine/tenofovir disoproxil fumarate
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INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT Emtricitabine/Tenofovir Disoproxil Fumarate
Composition:
Active substances: emtricitabine; tenofovir disoproxil fumarate;
One film-coated tablet contains 200 mg of emtricitabine and 300 mg of tenofovir disoproxil fumarate, equivalent to 245 mg of tenofovir disoproxil;
Excipients: microcrystalline cellulose; lactose monohydrate; sodium croscarmellose; magnesium stearate; Opadry II 31K80956 Blue (lactose monohydrate; hypromellose; titanium dioxide (E 171); triacetin; indigo carmine (E 132) aluminium lake).
Pharmaceutical form. Film-coated tablets.
Main physicochemical properties: blue, oval-shaped, film-coated tablets, debossed with «M117» on one side and smooth on the other.
Pharmacotherapeutic group.
Direct-acting antiviral agents for systemic use. Antiviral agents for treatment of HIV infection in combination. ATC code J05A R03.
Pharmacological properties.
Pharmacodynamics.
Mechanism of action
Emtricitabine is a nucleoside analogue of cytidine. Tenofovir disoproxil fumarate is converted in vivo to tenofovir, a nucleotide analogue of adenosine monophosphate. Both emtricitabine and tenofovir exhibit activity specific to human immunodeficiency virus (HIV-1 and HIV-2) and hepatitis B virus.
Emtricitabine and tenofovir are phosphorylated by cellular enzymes to form emtricitabine triphosphate and tenofovir diphosphate, respectively. In vitro studies have shown that both emtricitabine and tenofovir can be fully phosphorylated when combined together in cells. Emtricitabine triphosphate and tenofovir diphosphate competitively inhibit HIV-1 reverse transcriptase, resulting in chain termination of DNA synthesis.
Both emtricitabine triphosphate and tenofovir diphosphate are weak inhibitors of mammalian DNA polymerases; there is no evidence of mitochondrial toxicity in vitro or in vivo.
Antiviral activity in vitro
Synergistic antiviral activity has been observed with the combination of emtricitabine and tenofovir in vitro. Additive effects have also been observed in combination studies with protease inhibitors and with nucleoside and non-nucleoside reverse transcriptase inhibitors of HIV.
Resistance
In vitro. Resistance has been observed in vitro and in some HIV-1-infected patients due to the development of M184V/I mutations with emtricitabine or K65R mutation with tenofovir. Emtricitabine-resistant viruses with M184V/I mutations were cross-resistant to lamivudine but remained sensitive to didanosine, stavudine, tenofovir, and zidovudine. The K65R mutation may also be selected by abacavir or didanosine and leads to reduced susceptibility to these agents as well as to lamivudine, emtricitabine, and tenofovir. HIV-1-infected patients with the K65R mutation should avoid the use of tenofovir disoproxil fumarate. Additionally, the K70E substitution in HIV-1 reverse transcriptase is selected by tenofovir and results in a significant reduction in susceptibility to abacavir, emtricitabine, lamivudine, and tenofovir.
HIV-1-infected patients who had 3 or more thymidine analogue-associated mutations (TAMs), including either the M41L or L210W reverse transcriptase mutation, showed reduced susceptibility to tenofovir disoproxil fumarate.
In vivo. In an open-label, randomized clinical trial (GS-01-934) in antiretroviral treatment-naïve patients, genotyping was performed on HIV-1 isolates from plasma of all patients with confirmed HIV RNA > 400 copies/mL at week 48, 96, or 144, or at the time of premature discontinuation of study drug. As of week 144:
- According to the analysis performed, the M184V/I mutation developed in 2 of 19 (10.5%) isolates from patients receiving emtricitabine/tenofovir disoproxil fumarate/efavirenz and in 10 of 29 (34.5%) isolates analyzed from patients receiving lamivudine/zidovudine/efavirenz (p < 0.05, Fisher's exact test comparing patients receiving emtricitabine + tenofovir disoproxil fumarate versus lamivudine/zidovudine).
- None of the analyzed viruses contained the K65R or K70E mutation.
- Genotypic resistance to efavirenz, primarily the K103N viral mutation, developed in 13 of 19 (68%) patients receiving emtricitabine/tenofovir disoproxil fumarate/efavirenz compared to 21 of 29 (72%) patients in the comparator group.
Pediatric population
The safety and efficacy of the medicinal product in children under 12 years of age have not been established.
Clinical trials of the medicinal product have not been conducted in pediatric patients with HIV-1. The clinical efficacy and safety of the medicinal product have been established in studies using emtricitabine and tenofovir disoproxil fumarate as monotherapy.
Emtricitabine studies
In the majority of infants and children aged 4 months and older receiving emtricitabine, complete suppression of plasma HIV-1 RNA was achieved or maintained at 48 weeks (89% achieved ≤ 400 copies/mL and 77% achieved ≤ 50 copies/mL).
Tenofovir disoproxil fumarate studies
In study GS-US-104-0321, 87 HIV-1-infected patients aged 12 to 18 years were randomized to receive tenofovir disoproxil fumarate (n = 45) or placebo (n = 42) in combination with an optimized background regimen (OBR) for 48 weeks. Due to study limitations, a benefit of tenofovir disoproxil fumarate over placebo based on plasma HIV-1 RNA levels at week 24 was not demonstrated; however, benefit in adolescent patients is expected based on extrapolation from adult data and comparative pharmacokinetic data (see section "Pharmacokinetics").
In patients receiving tenofovir disoproxil fumarate or placebo, mean Z-scores for bone mineral density (BMD) of the lumbar spine were -1.004 and -0.809, and mean Z-scores for whole-body BMD were -0.866 and -0.584 for tenofovir disoproxil fumarate and placebo, respectively. Mean changes at week 48 (end of the double-blind phase) were -0.215 and -0.165 for lumbar spine BMD Z-scores and -0.254 and -0.179 for whole-body BMD Z-scores with tenofovir disoproxil fumarate or placebo, respectively. Mean BMD coefficient was lower with tenofovir disoproxil fumarate compared to placebo. At week 48, six adolescents receiving tenofovir disoproxil fumarate and one receiving placebo had significant loss of lumbar spine BMD (defined as > 4%). In 28 patients who received tenofovir disoproxil fumarate for 96 weeks, BMD Z-scores decreased to -0.341 for the lumbar spine and -0.458 for the whole body.
In study GS-US-104-0352, 97 previously treated patients aged 2 to 12 years with stable viral suppression on a regimen containing stavudine or zidovudine were randomized to replace stavudine or zidovudine with tenofovir disoproxil fumarate (n = 48) or continue their original regimen (n = 49) for 48 weeks. At week 48, 83% of patients in the tenofovir disoproxil fumarate treatment group and 92% in the stavudine or zidovudine treatment group had HIV-1 RNA concentration < 400 copies/mL. The difference in the proportion of patients with HIV-1 RNA < 400 copies/mL at week 48 was primarily influenced by a higher number of patients discontinuing treatment in the tenofovir disoproxil fumarate group. When missing data were excluded, 91% of patients in the tenofovir disoproxil fumarate treatment group and 94% in the stavudine or zidovudine treatment group had HIV-1 RNA concentration < 400 copies/mL at week 48.
Cases of decreased BMD have been reported in pediatric patients. In patients receiving tenofovir disoproxil fumarate or stavudine or zidovudine, mean Z-scores for lumbar spine BMD were -1.034 and -0.498, and mean Z-scores for whole-body BMD were -0.471 and -0.386, respectively. Mean changes at week 48 (end of the randomized phase) were 0.032 and 0.087 for lumbar spine BMD Z-scores and -0.184 and -0.027 for whole-body BMD Z-scores with tenofovir disoproxil fumarate and stavudine or zidovudine, respectively. Mean changes in the lumbar spine at week 48 were similar between the tenofovir disoproxil fumarate and stavudine or zidovudine treatment groups. The overall coefficient of change in whole-body BMD in the tenofovir disoproxil fumarate treatment group was lower than in the stavudine or zidovudine treatment group. Treatment with tenofovir disoproxil fumarate alone, without stavudine or zidovudine, resulted in significant (> 4%) loss of lumbar spine BMD at week 48. BMD Z-scores decreased by -0.012 for the lumbar spine and -0.338 for the whole body in 64 individuals who received tenofovir disoproxil fumarate for 96 weeks. BMD Z-scores were not corrected for patient height and body weight.
In study GS-US-104-0352, 8 of 89 pediatric patients (9.0%) exposed to tenofovir disoproxil fumarate discontinued the clinical trial due to urinary system disorders. Clinical laboratory assessments for proximal renal tubulopathy were conducted in five patients (5.6%), four of whom discontinued tenofovir disoproxil fumarate treatment (mean duration of tenofovir disoproxil fumarate exposure – 331 weeks).
Pharmacokinetics.
Absorption
Bioequivalence of one film-coated tablet of the medicinal product and one 200 mg emtricitabine hard capsule + one 300 mg film-coated tablet of tenofovir disoproxil fumarate was established after single-dose administration in the fasting state to healthy volunteers. After oral administration of the medicinal product to healthy volunteers, emtricitabine and tenofovir disoproxil fumarate were rapidly absorbed, and tenofovir disoproxil fumarate was converted to tenofovir. Maximum concentrations (Cmax) of emtricitabine and tenofovir in plasma are reached within 0.5–3.0 hours after administration in the fasting state. Administration of the medicinal product with food delayed the time to maximum concentration of tenofovir by approximately three-quarters of an hour. The area under the concentration-time curve (AUC) and Cmax of tenofovir increased by approximately 35% and 15%, respectively, when administered with a high-fat or light meal compared to fasting. To optimize tenofovir absorption, it is recommended to take the medicinal product with food.
Distribution
After intravenous administration, the volume of distribution of emtricitabine and tenofovir was approximately 1.4 L/kg and 800 mL/kg, respectively. After oral administration of emtricitabine or tenofovir disoproxil fumarate, emtricitabine and tenofovir are extensively distributed throughout the body. In vitro, plasma protein binding of emtricitabine in human plasma was < 4% and independent of concentration over the range of 0.02 mcg/mL to 200 mcg/mL. In vitro, binding of tenofovir to plasma proteins or serum proteins was less than 0.7% and 7.2%, respectively, over the concentration range of tenofovir from 0.01 mcg/mL to 25 mcg/mL.
Biotransformation
Metabolism of emtricitabine is limited. Biotransformation of emtricitabine includes oxidation of the thiol moiety to form 3'-sulfoxide diastereomers (approximately 9% of dose) and conjugation with glucuronic acid to form 2'-O-glucuronide (approximately 4% of dose). In vitro studies showed that neither tenofovir disoproxil fumarate nor tenofovir are substrates of CYP450 enzymes. Emtricitabine also did not inhibit uridine-5'-diphosphoglucuronosyltransferase, the enzyme responsible for glucuronidation.
Elimination
Emtricitabine is primarily eliminated by the kidneys, with the full dose recovered in urine (approximately 86%) and feces (approximately 14%). Thirteen percent of the emtricitabine dose is excreted in urine as three metabolites. Systemic clearance of emtricitabine averages 307 mL/min. After oral administration, the elimination half-life of emtricitabine is approximately 10 hours.
Tenofovir is primarily eliminated by the kidneys via both glomerular filtration and active tubular transport; approximately 70–80% of the dose is excreted unchanged in urine after intravenous administration. Apparent mean clearance of tenofovir is approximately 307 mL/min. Renal clearance is approximately 210 mL/min, exceeding the glomerular filtration rate, indicating that tubular secretion is an important component of tenofovir elimination. After oral administration, the elimination half-life of tenofovir is approximately 12 to 18 hours.
Elderly patients
Pharmacokinetic studies of emtricitabine or tenofovir in elderly patients (aged 65 years and older) have not been conducted.
Gender
Pharmacokinetics of emtricitabine and tenofovir are similar in male and female patients.
Ethnic origin
There is no clinically significant pharmacokinetic difference for emtricitabine based on patient ethnicity. The pharmacokinetics of tenofovir has not been specifically studied in different ethnic groups.
Children
Pharmacokinetic studies of the medicinal product have not been conducted in children and adolescents (under 18 years of age). Steady-state pharmacokinetics of tenofovir were determined in 8 HIV-1-infected adolescent patients (12–18 years) with body weight ≥ 35 kg and in 23 HIV-1-infected children (aged 2 to 12 years). Exposure to tenofovir in pediatric patients receiving an oral dose of tenofovir disoproxil 245 mg (as fumarate) or 6.5 mg/kg tenofovir disoproxil (as fumarate) up to a maximum dose of 245 mg was similar to exposure in adults receiving daily doses of tenofovir disoproxil 245 mg (as fumarate). Pharmacokinetic studies with tenofovir disoproxil (as fumarate) have not been conducted in children under 2 years of age. Pharmacokinetics of emtricitabine in infants, young children, and adolescents (aged 4 months to 18 years) are similar to those observed in adults.
The pharmacokinetics of emtricitabine and tenofovir (as tenofovir disoproxil fumarate) are expected to be similar in HIV-1-infected and uninfected adolescents based on similar exposure of emtricitabine and tenofovir in HIV-1-infected adolescents and adults, as well as similar exposure of emtricitabine and tenofovir in HIV-1-infected and uninfected adults.
Renal impairment
There are insufficient pharmacokinetic data for emtricitabine and tenofovir in patients with renal impairment following co-administration of these medicinal products either separately or as part of this medicinal product. Pharmacokinetic parameters were primarily determined after single doses of 200 mg emtricitabine or 245 mg tenofovir disoproxil in HIV-uninfected patients with varying degrees of renal impairment. The degree of renal impairment was defined according to baseline creatinine clearance (CrCl) values (normal renal function: CrCl > 80 mL/min; mild impairment: CrCl = 50–79 mL/min; moderate impairment: CrCl = 30–49 mL/min; severe impairment: CrCl = 10–29 mL/min). Mean (% CV – coefficient of variation) emtricitabine exposure increased from 12 mcg•h/mL (25%) in patients with normal renal function to 20 mcg•h/mL (6%), 25 mcg•h/mL (23%), and 34 mcg•h/mL (6%) in patients with mild, moderate, and severe renal impairment, respectively.
Mean (% CV) tenofovir exposure increased from 2,185 ng•h/mL (12%) in patients with normal renal function to 3,064 ng•h/mL (30%), 6,009 ng•h/mL (42%), and 15,985 ng•h/mL (45%) in patients with mild, moderate, and severe renal impairment, respectively.
An increased dosing interval of the medicinal product in HIV-infected patients with moderate renal impairment is expected to result, compared to patients with normal renal function, in increased plasma Cmax and decreased minimum concentration (Cmin).
In patients with end-stage renal disease (ESRD) requiring hemodialysis, drug exposure was significantly increased: up to 53 mcg•h/mL (19%) for emtricitabine over 72 hours and up to 42,857 ng•h/mL (29%) for tenofovir over 48 hours.
A small clinical trial evaluating the safety, antiviral activity, and pharmacokinetics of tenofovir disoproxil fumarate in combination with emtricitabine was conducted in HIV-infected patients with renal impairment. In a subgroup of patients with baseline CrCl of 50–60 mL/min, once-daily administration of the medicinal product resulted in a 2- to 4-fold increase in tenofovir exposure and worsening of renal function.
The pharmacokinetics of emtricitabine and tenofovir in pediatric patients with renal impairment have not been studied. There are no data to provide dosing recommendations (see sections "Special precautions" and "Dosage and administration").
Hepatic impairment
The pharmacokinetics of the medicinal product in patients with hepatic impairment have not been studied.
Pharmacokinetics of emtricitabine have not been studied in patients without hepatitis B virus (HBV) infection and with varying degrees of hepatic impairment. Overall, emtricitabine pharmacokinetics in HBV-infected patients were similar to those in patients without HBV and in HIV-infected patients.
A single 245 mg dose of tenofovir disoproxil was administered to HIV-uninfected patients with varying degrees of hepatic impairment classified according to the Child-Pugh-Turcotte (CPT) score. Pharmacokinetic parameters of tenofovir were not significantly altered in patients with hepatic impairment, indicating that dose adjustment is not required for these patients. Mean (% CV) values of Cmax and AUC0-∞ for tenofovir were 223 ng/mL (34.8%) and 2,050 ng•h/mL (50.8%), respectively, in patients without hepatic impairment compared to 289 ng/mL (46%) and 2,310 ng•h/mL (43.5%) in patients with moderate hepatic impairment and 305 ng/mL (24.8%) and 2,740 ng•h/mL (44%) in patients with severe hepatic impairment.
Clinical characteristics.
Indications.
The medicinal product is indicated in combination antiretroviral therapy for the treatment of HIV-1 infected adults. The product is also indicated for the treatment of HIV-1 infected adolescents aged 12 to 18 years with resistance to nucleoside reverse transcriptase inhibitors or toxicity precluding the use of first-line agents (see section "Pharmacodynamics").
Contraindications.
Hypersensitivity to the active substances or to any of the excipients of the medicinal product.
Contraindicated in children under 12 years of age.
Interaction with other medicinal products and other types of interactions.
Interaction studies have been conducted only in adults.
Since this medicinal product contains emtricitabine and tenofovir disoproxil fumarate, any interactions observed when these substances were administered separately may also occur with the use of this medicinal product. The steady-state pharmacokinetics of emtricitabine and tenofovir are not altered when emtricitabine and tenofovir disoproxil fumarate are administered together, compared to administration of each agent separately.
In vitro and clinical pharmacokinetic interaction studies indicate a low potential for CYP450-mediated interactions between emtricitabine and tenofovir disoproxil fumarate with other medicinal products.
Concomitant use not recommended
The medicinal product should not be taken concomitantly with other medicinal products containing emtricitabine, tenofovir disoproxil (as fumarate), tenofovir alafenamide, or other cytidine analogues such as lamivudine (see section "Special precautions for use"). The medicinal product should not be taken concomitantly with adefovir dipivoxil.
Didanosine. Concomitant administration of the medicinal product and didanosine is not recommended (see section "Special precautions for use" and Table 1).
Medicinal products eliminated by the kidneys. Since emtricitabine and tenofovir are primarily eliminated by the kidneys, concomitant administration of the medicinal product with other medicinal products eliminated via active tubular secretion (e.g., cidofovir) may lead to increased serum concentrations of emtricitabine and/or concomitantly administered medicinal products due to competition for this elimination pathway.
Concomitant or recent use of the medicinal product with nephrotoxic medicinal products should be avoided, including aminoglycosides, amphotericin B, foscarnet, ganciclovir, pentamidine, vancomycin, cidofovir, or interleukin-2 (see section "Special precautions for use").
Other interactions
Interactions between the medicinal product or its individual component(s) and other medicinal products are presented in Table 1 (increases are indicated by "↑", decreases by "↓", no change by "↔", twice daily by "b.i.d.", and once daily by "q.d."). Where available, 90% confidence intervals are indicated in parentheses.
Table 1
Interaction between the medicinal product Emtricitabine/Tenofovir disoproxil fumarate
and its component(s) and other medicinal products
| Medicinal products by therapeutic area |
Effect on drug concentration levels Mean percentage change in AUC, Cmax, Cmin with 90% confidence intervals if available (mechanism) |
Recommendations for concomitant use with the medicinal product (emtricitabine 200 mg, tenofovir disoproxil fumarate 300 mg) |
| ANTIMICROBIAL AGENTS |
||
| Antiretroviral |
||
| Protease inhibitors |
||
| Atazanavir/ritonavir/tenofovir disoproxil fumarate (300 mg q.d./100 mg q.d./300 mg q.d.) |
Atazanavir: AUC: ↓ 25 % (↓ 42 to ↓ 3) Cmax: ↓ 28 % (↓ 50 to ↑ 5) Cmin: ↓ 26 % (↓ 46 to ↑ 10) Tenofovir: AUC: ↑ 37 % Cmax: ↑ 34 % Cmin: ↑ 29 % |
Dose adjustment is not recommended. Increased tenofovir exposure may enhance tenofovir-related adverse reactions, including renal impairment. Renal function should be monitored closely (see section "Special warnings and precautions for use"). |
| Atazanavir/ritonavir/emtricitabine |
Interaction not studied. |
|
| Darunavir/ritonavir/tenofovir disoproxil fumarate (300 mg q.d./100 mg q.d./300 mg q.d.) |
Darunavir: AUC: ↔ Cmin: ↔ Tenofovir: AUC: ↑ 22 % Cmin: ↑ 37 % |
Dose adjustment is not recommended. Increased tenofovir exposure may enhance tenofovir-related adverse reactions, including renal impairment. Renal function should be monitored closely (see section "Special warnings and precautions for use"). |
| Darunavir/ritonavir/emtricitabine |
Interaction not studied. |
|
| Lopinavir/ritonavir/tenofovir disoproxil fumarate (400 mg b.i.d./100 mg b.i.d./300 mg q.d.) |
Lopinavir/ritonavir: AUC: ↔ Cmax: ↔ Cmin: ↔ Tenofovir: AUC: ↑ 32 % (↑ 25 to ↑ 38) Cmax: ↔ Cmin: ↑ 51 % (↑ 37 to ↑ 66) |
Dose adjustment is not recommended. Increased tenofovir exposure may enhance tenofovir-related adverse reactions, including renal impairment. Renal function should be monitored closely (see section "Special warnings and precautions for use"). |
| Lopinavir/ritonavir/emtricitabine |
Interaction not studied. |
|
| Nucleoside reverse transcriptase inhibitors (NRTIs) |
||
| Didanosine/tenofovir disoproxil fumarate |
Concomitant administration of tenofovir disoproxil fumarate and didanosine is not recommended, as it leads to a 40–60 % increase in systemic exposure to didanosine. |
Concomitant use of this medicinal product with didanosine is not recommended (see section "Special warnings and precautions for use"). Increased systemic exposure to didanosine may increase the risk of didanosine-related adverse reactions. Rare, sometimes fatal cases of pancreatitis and lactic acidosis have been reported. Concomitant use of tenofovir disoproxil and didanosine at a dose of 400 mg daily has been associated with significant decreases in CD4 lymphocyte counts, possibly due to increased intracellular interaction of phosphorylated (i.e. active) didanosine. A reduced dose of didanosine 250 mg, used concomitantly with tenofovir disoproxil, has been associated with high rates of virological failure during several controlled combination therapies for the treatment of HIV-1 infection. |
| Didanosine/emtricitabine |
Interaction not studied |
|
| Lamivudine/tenofovir disoproxil fumarate |
Lamivudine: AUC: ↓ 3 % (↓ 8 to ↑ 15) Cmax: ↓ 24 % (↓ 44 to ↓ 12) Cmin: NC Tenofovir: AUC: ↓ 4 % (↓ 15 to ↑ 8) Cmax: ↓ 102 % (↓ 96 to ↑ 108) Cmin: NC |
Lamivudine and this medicinal product should not be administered concomitantly (see section "Special warnings and precautions for use"). |
| Efavirenz/tenofovir disoproxil fumarate |
Efavirenz: AUC: ↓ 4 % (↓ 7 to ↓ 1) Cmax: ↓ 4 % (↓ 9 to ↑ 2) Cmin: NC Tenofovir: AUC: ↓ 1 % (↓ 8 to ↑ 6) Cmax: ↑ 7 % (↓ 6 to ↑ 22) Cmin: NC |
No dose adjustment of efavirenz is required. |
| ANTIMICROBIAL AGENTS |
||
| Antiviral agents for hepatitis B virus (HBV) |
||
| Adefovir dipivoxil/tenofovir disoproxil fumarate |
Adefovir dipivoxil: AUC: ↓ 11 % (↓ 14 to ↓ 7) Cmax: ↓ 7 % (↓ 13 to ↓ 0) Cmin: NC Tenofovir: AUC: ↓ 2 % (↓ 5 to ↑ 0) Cmax: ↓ 1 % (↓ 7 to ↑ 6) Cmin: NC |
Adefovir dipivoxil and this medicinal product should not be administered concomitantly (see section "Special warnings and precautions for use"). |
| Antiviral agents for hepatitis C virus (HCV) |
||
| Ledipasvir/sofosbuvir (90 mg/400 mg q.d.) + atazanavir/ritonavir (300 mg q.d./100 mg q.d.) + emtricitabine/tenofovir disoproxil fumarate (200 mg/300 mg q.d.)1 |
Ledipasvir: AUC: ↑ 96 % (↑ 74 to ↑ 121) Cmax: ↑ 68 % (↑ 54 to ↑ 84) Cmin: ↑ 118 % (↑ 91 to ↑ 150) Sofosbuvir: AUC: ↔ Cmax: ↔ GS-3310072: AUC: ↔ Cmax: ↔ Cmin: ↑ 42 % (↑ 34 to ↑ 49) Atazanavir: AUC: ↔ Cmax: ↔ Cmin: ↑ 63 % (↑ 45 to ↑ 84) Ritonavir: AUC: ↔ Cmax: ↔ Cmin: ↑ 45 % (↑ 27 to ↑ 64) Emtricitabine: AUC: ↔ Cmax: ↔ Cmin: ↔ Tenofovir: AUC: ↔ Cmax: ↑ 47 % (↑ 37 to ↑ 58) Cmin: ↑ 47 % (↑ 38 to ↑ 57) |
Elevated plasma tenofovir concentrations resulting from concomitant administration of tenofovir disoproxil fumarate, ledipasvir/sofosbuvir, and atazanavir/ritonavir may enhance adverse reactions associated with tenofovir disoproxil fumarate, including renal impairment. The safety of tenofovir disoproxil fumarate when used with ledipasvir/sofosbuvir and a pharmacokinetic booster (e.g., ritonavir or cobicistat) has not been established. This combination should be prescribed only with frequent monitoring of renal function and in the absence of alternative therapy (see section "Special warnings and precautions for use"). |
| Ledipasvir/sofosbuvir (90 mg/400 mg q.d.) + darunavir/ritonavir (800 mg q.d./100 mg q.d.) + emtricitabine/tenofovir disoproxil fumarate (200 mg/300 mg q.d.)1 |
Ledipasvir: AUC: ↔ Cmax: ↔ Cmin: ↔ Sofosbuvir: AUC: ↓ 27 % (↓ 35 to ↓ 18) Cmax: ↓ 37 % (↓ 48 to ↓ 25) GS-3310072: AUC: ↔ Cmax: ↔ Cmin: ↔ Darunavir: AUC: ↔ Cmax: ↔ Cmin: ↔ Ritonavir: AUC: ↔ Cmax: ↔ Cmin: ↑ 48 % (↑ 34 to ↑ 63) Emtricitabine: AUC: ↔ Cmax: ↔ Cmin: ↔ Tenofovir: AUC: ↑ 50 % (↑ 42 to ↑ 59) Cmax: ↑ 64 % (↑ 54 to ↑ 74) Cmin: ↑ 59 % (↑ 49 to ↑ 70) |
Elevated plasma tenofovir concentrations resulting from concomitant administration of tenofovir disoproxil fumarate, ledipasvir/sofosbuvir, and darunavir/ritonavir may enhance adverse reactions associated with tenofovir disoproxil fumarate, including renal impairment. The safety of tenofovir disoproxil fumarate when used with ledipasvir/sofosbuvir and a pharmacokinetic booster (e.g., ritonavir or cobicistat) has not been established. This combination should be prescribed only with frequent monitoring of renal function and in the absence of alternative therapy (see section "Special warnings and precautions for use"). |
| Ledipasvir/sofosbuvir (90 mg/400 mg q.d.) + efavirenz/emtricitabine/tenofovir disoproxil fumarate (600 mg/200 mg/300 mg q.d.) |
Ledipasvir: AUC: ↓ 34 % (↓ 41 to ↓ 25) Cmax: ↓ 34 % (↓ 41 to ↑ 25) Cmin: ↓ 34 % (↓ 43 to ↑ 24) Sofosbuvir: AUC: ↔ Cmax: ↔ GS-3310072: AUC: ↔ Cmax: ↔ Cmin: ↔ Efavirenz: AUC: ↔ Cmax: ↔ Cmin: ↔ Emtricitabine: AUC: ↔ Cmax: ↔ Cmin: ↔ Tenofovir: AUC: ↑ 98 % (↑ 77 to ↑ 123) Cmax: ↑ 79 % (↑ 56 to ↑ 104) Cmin: ↑ 163 % (↑ 137 to ↑ 197) |
Dose adjustment is not recommended. Increased tenofovir dosage may enhance adverse reactions associated with tenofovir disoproxil fumarate, including renal impairment. Renal function should be monitored closely (see section "Special warnings and precautions for use"). |
| Ledipasvir/sofosbuvir (90 mg/400 mg q.d.) + emtricitabine/rilpivirine/tenofovir disoproxil fumarate (200 mg/25 mg/300 mg q.d.) |
Ledipasvir: AUC: ↔ Cmax: ↔ Cmin: ↔ Sofosbuvir: AUC: ↔ Cmax: ↔ GS-3310072: AUC: ↔ Cmax: ↔ Cmin: ↔ Emtricitabine: AUC: ↔ Cmax: ↔ Cmin: ↔ Rilpivirine: AUC: ↔ Cmax: ↔ Cmin: ↔ Tenofovir: AUC: ↑ 40 % (↑ 31 to ↑ 50) Cmax: ↔ Cmin: ↑ 91 % (↑ 74 to ↑ 110) |
Dose adjustment is not recommended. Increased tenofovir dosage may enhance adverse reactions associated with tenofovir disoproxil fumarate, including renal impairment. Renal function should be monitored closely (see section "Special warnings and precautions for use"). |
| Ledipasvir/sofosbuvir (90 mg/400 mg q.d.) + dolutegravir (50 mg q.d.) + emtricitabine/tenofovir disoproxil fumarate (200 mg/300 mg q.d.) |
Sofosbuvir: AUC: ↔ Cmax: ↔ GS-3310072 AUC: ↔ Cmax: ↔ Cmin: ↔ Ledipasvir: AUC: ↔ Cmax: ↔ Cmin: ↔ Dolutegravir: AUC: ↔ Cmax: ↔ Cmin: ↔ Emtricitabine: AUC: ↔ Cmax: ↔ Cmin: ↔ Tenofovir: AUC: ↑ 65 % (↑ 59 to ↑ 71) Cmax: ↑ 61 % (↑ 51 to ↑ 72) Cmin: ↑ 115 % (↑ 105 to ↑ 126) |
Dose adjustment is not required. Increased tenofovir dosage may enhance adverse reactions associated with tenofovir disoproxil fumarate, including renal impairment. Renal function should be monitored closely (see section "Special warnings and precautions for use"). |
| Sofosbuvir/velpatasvir (400 mg/100 mg q.d.) + atazanavir/ritonavir (300 mg q.d./100 mg q.d.) + emtricitabine/tenofovir disoproxil fumarate (200 mg/300 mg q.d.) |
Sofosbuvir: AUC: ↔ Cmax: ↔ GS-3310072: AUC: ↔ Cmax: ↔ Cmin: ↑ 42 % (↑ 37 to ↑ 49) Velpatasvir: AUC: ↑ 142 % (↑ 123 to ↑ 164) Cmax: ↑ 55 % (↑ 41 to ↑ 71) Cmin: ↑ 301 % (↑ 257 to ↑ 350) Atazanavir: AUC: ↔ Cmax: ↔ Cmin: ↑ 39 % (↑ 20 to ↑ 61) Ritonavir: AUC: ↔ Cmax: ↔ Cmin: ↑ 29 % (↑ 15 to ↑ 44) Emtricitabine: AUC: ↔ Cmax: ↔ Cmin: ↔ Tenofovir: AUC: ↔ Cmax: ↑ 55 % (↑ 43 to ↑ 68) Cmin: ↑ 39 % (↑ 31 to ↑ 48) |
Elevated plasma tenofovir concentrations resulting from concomitant administration of tenofovir disoproxil fumarate, sofosbuvir/velpatasvir, and atazanavir/ritonavir may enhance adverse reactions associated with tenofovir disoproxil fumarate, including renal impairment. The safety of tenofovir disoproxil fumarate when used with sofosbuvir/velpatasvir and a pharmacokinetic booster (e.g., ritonavir or cobicistat) has not been established. This combination should be prescribed only with frequent monitoring of renal function (see section "Special warnings and precautions for use"). |
| Sofosbuvir/velpatasvir (400 mg/100 mg q.d.) + darunavir/ritonavir (800 mg q.d./100 mg q.d.) + emtricitabine/tenofovir disoproxil fumarate (200 mg/300 mg q.d.) |
Sofosbuvir: AUC: ↓ 28 % (↓ 34 to ↓ 20) Cmax: ↓ 38 % (↓ 46 to ↓ 29) GS-3310072: AUC: ↔ Cmax: ↔ Cmin: ↔ Velpatasvir: AUC: ↔ Cmax: ↓ 24 % (↓ 35 to ↓ 11) Cmin: ↔ Darunavir: AUC: ↔ Cmax: ↔ Cmin: ↔ Ritonavir: AUC: ↔ Cmax: ↔ Cmin: ↔ Emtricitabine: AUC: ↔ Cmax: ↔ Cmin: ↔ Tenofovir: AUC: ↑ 39 % (↑ 33 to ↑ 44) Cmax: ↑ 55 % (↑ 45 to ↑ 66) Cmin: ↑ 52 % (↑ 45 to ↑ 59) |
Elevated plasma tenofovir concentrations resulting from concomitant administration of tenofovir disoproxil fumarate, sofosbuvir/velpatasvir, and darunavir/ritonavir may enhance adverse reactions associated with tenofovir disoproxil fumarate, including renal impairment. The safety of tenofovir disoproxil fumarate when used with sofosbuvir/velpatasvir and a pharmacokinetic booster (e.g., ritonavir or cobicistat) has not been established. This combination should be prescribed only with frequent monitoring of renal function (see section "Special warnings and precautions for use"). |
| Sofosbuvir/velpatasvir (400 mg/100 mg q.d.) + lopinavir/ritonavir (800 mg q.d./200 mg q.d.) + emtricitabine/tenofovir disoproxil fumarate (200 mg/300 mg q.d.) |
Sofosbuvir: AUC: ↓ 29 % (↓ 36 to ↓ 22) Cmax: ↓ 41 % (↓ 51 to ↓ 29) GS-3310072: AUC: ↔ Cmax: ↔ Cmin: ↔ Velpatasvir: AUC: ↔ Cmax: ↓ 30 % (↓ 41 to ↓ 17) Cmin: ↑ 63 % (↑ 43 to ↑ 85) Lopinavir: AUC: ↔ Cmax: ↔ Cmin: ↔ Ritonavir: AUC: ↔ Cmax: ↔ Cmin: ↔ Emtricitabine: AUC: ↔ Cmax: ↔ Cmin: ↔ Tenofovir: AUC: ↔ Cmax: ↑ 42 % (↑ 27 to ↑ 57) Cmin: ↔ |
Elevated plasma tenofovir concentrations resulting from concomitant administration of tenofovir disoproxil fumarate, sofosbuvir/velpatasvir, and lopinavir/ritonavir may enhance adverse reactions associated with tenofovir disoproxil fumarate, including renal impairment. The safety of tenofovir disoproxil fumarate when used with sofosbuvir/velpatasvir and a pharmacokinetic booster (e.g., ritonavir or cobicistat) has not been established. This combination should be prescribed only with frequent monitoring of renal function (see section "Special warnings and precautions for use"). |
| Sofosbuvir/velpatasvir (400 mg/100 mg q.d.) + raltegravir (400 mg b.i.d.) + emtricitabine/tenofovir disoproxil fumarate (200 mg/300 mg q.d.) |
Sofosbuvir: AUC: ↔ Cmax: ↔ GS-3310072: AUC: ↔ Cmax: ↔ Cmin: ↔ Velpatasvir: AUC: ↔ Cmax: ↔ Cmin: ↔ Raltegravir: AUC: ↔ Cmax: ↔ Cmin: ↓ 21 % (↓ 58 to ↑ 48) Emtricitabine: AUC: ↔ Cmax: ↔ Cmin: ↔ Tenofovir: AUC: ↑ 40 % (↑ 34 to ↑ 45) Cmax: ↑ 46 % (↑ 39 to ↑ 54) Cmin: ↑ 70 % (↑ 61 to ↑ 79) |
Dose adjustment is not recommended. Increased tenofovir dosage may enhance adverse reactions associated with tenofovir disoproxil fumarate, including renal impairment. Renal function should be monitored closely (see section "Special warnings and precautions for use"). |
| Sofosbuvir/velpatasvir (400 mg/100 mg q.d.) + efavirenz/emtricitabine/tenofovir disoproxil fumarate (600 mg/200 mg/300 mg q.d.) |
Sofosbuvir: AUC: ↔ Cmax: ↑ 38 % (↑ 14 to ↑ 67) GS-3310072: AUC: ↔ Cmax: ↔ Cmin: ↔ Velpatasvir: AUC: ↓ 53 % (↓ 61 to ↓ 43) Cmax: ↓ 47 % (↓ 57 to ↓ 36) Cmin: ↓ 57 % (↓ 64 to ↓ 48) Efavirenz: AUC: ↔ Cmax: ↔ Cmin: ↔ Emtricitabine: AUC: ↔ Cmax: ↔ Cmin: ↔ Tenofovir: AUC: ↑ 81 % (↑ 68 to ↑ 94) Cmax: ↑ 77 % (↑ 53 to ↑ 104) Cmin: ↑ 121 % (↑ 100 to ↑ 143) |
Concomitant administration of sofosbuvir/velpatasvir and efavirenz reduces plasma concentrations of velpatasvir. Concomitant use of sofosbuvir/velpatasvir with efavirenz-containing regimens is not recommended. |
| Sofosbuvir/velpatasvir (400 mg/100 mg q.d.) + emtricitabine/rilpivirine/tenofovir disoproxil fumarate (200 mg/25 mg/300 mg q.d.) |
Sofosbuvir: AUC: ↔ Cmax: ↔ GS-3310072: AUC: ↔ Cmax: ↔ Cmin: ↔ Velpatasvir: AUC: ↔ Cmax: ↔ Cmin: ↔ Emtricitabine: AUC: ↔ Cmax: ↔ Cmin: ↔ Rilpivirine: AUC: ↔ Cmax: ↔ Cmin: ↔ Tenofovir: AUC: ↑ 40 % (↑ 34 to ↑ 46) Cmax: ↑ 44 % (↑ 33 to ↑ 55) Cmin: ↑ 84 % (↑ 76 to ↑ 92) |
Dose adjustment is not recommended. Increased tenofovir dosage may enhance adverse reactions associated with tenofovir disoproxil fumarate, including renal impairment. Renal function should be monitored closely (see section "Special warnings and precautions for use"). |
| Sofosbuvir/velpatasvir/voxilaprevir (400 mg/100 mg/100 mg + 100 mg q.d.)3 + darunavir (800 mg q.d.) + ritonavir (100 mg q.d.) + emtricitabine/tenofovir disoproxil fumarate (200 mg/300 mg q.d.) |
Sofosbuvir: AUC: ↔ Cmax: ↓ 30 % Cmin: N/A GS-3310072: AUC: ↔ Cmax: ↔ Cmin: N/A Velpatasvir: AUC: ↔ Cmax: ↔ Cmin: ↔ Voxilaprevir: AUC: ↑ 143 % Cmax: ↑ 72 % Cmin: ↑ 300 % Darunavir: AUC: ↔ Cmax: ↔ Cmin: ↓ 34 % Ritonavir: AUC: ↑ 45 % Cmax: ↑ 60 % Cmin: ↔ Emtricitabine: AUC: ↔ Cmax: ↔ Cmin: ↔ Tenofovir: AUC: ↑ 39 % Cmax: ↑ 48 % Cmin: ↑ 47 % |
Elevated plasma tenofovir concentrations resulting from concomitant administration of tenofovir disoproxil fumarate, sofosbuvir/velpatasvir/voxilaprevir, and darunavir/ritonavir may enhance adverse reactions associated with tenofovir disoproxil fumarate, including renal impairment. The safety of tenofovir disoproxil fumarate when used with sofosbuvir/velpatasvir/voxilaprevir and a pharmacokinetic booster (e.g., ritonavir or cobicistat) has not been established. This combination should be prescribed only with frequent monitoring of renal function (see section "Special warnings and precautions for use"). |
| Sofosbuvir (400 mg q.d.) + efavirenz/emtricitabine/tenofovir disoproxil fumarate (600 mg/200 mg/300 mg q.d.) |
Sofosbuvir: AUC: ↔ Cmax: ↓ 19 % (↓ 40 to ↑ 10) GS-3310072: AUC: ↔ Cmax: ↓ 23 % (↓ 30 to ↑ 16) Efavirenz: AUC: ↔ Cmax: ↔ Cmin: ↔ Emtricitabine: AUC: ↔ Cmax: ↔ Cmin: ↔ Tenofovir: AUC: ↔ Cmax: ↑ 25 % (↑ 8 to ↑ 45) Cmin: ↔ |
No dose adjustment required. |
| Ribavirin/tenofovir disoproxil fumarate |
Ribavirin: AUC: ↑ 26 % (↑ 20 to ↑ 32) Cmax: ↓ 5 % (↓ 11 to ↑ 1) Cmin: NC |
No ribavirin dose adjustment required. |
| Antiviral agents for herpes virus |
||
| Famciclovir/emtricitabine |
Famciclovir: AUC: ↓ 9 % (↓ 16 to ↓ 1) Cmax: ↓ 7 % (↓ 22 to ↑ 11) Cmin: NC Emtricitabine AUC: ↓ 7 % (↓ 13 to ↓ 1) Cmax: ↓ 11 % (↓ 20 to ↑ 1) Cmin: NC |
No famciclovir dose adjustment required. |
| Antimycobacterial agents |
||
| Rifampicin/tenofovir disoproxil fumarate |
Tenofovir: AUC: ↓ 12 % (↓ 16 to ↓ 8) Cmax: ↓ 16 % (↓ 22 to ↓ 10) Cmin: ↓ 15 % (↓ 12 to ↓ 9) |
No dose adjustment required. |
| ORAL CONTRACEPTIVES |
||
| Norgestimate/ethinylestradiol/ tenofovir disoproxil fumarate |
Norgestimate: AUC: ↓ 4 % (↓ 32 to ↑ 34) Cmax: ↓ 5 % (↓ 27 to ↑ 24) Cmin: NC Ethinylestradiol: AUC: ↓ 4 % (↓ 9 to ↑ 0) Cmax: ↓ 6 % (↓ 13 to ↑ 0) Cmin: ↓ 2 % (↓ 9 to ↑ 6) |
No dose adjustment of norgestimate/ ethinylestradiol required. |
| IMMUNOSUPPRESSANTS |
||
| Tacrolimus/tenofovir disoproxil fumarate/emtricitabine |
Tacrolimus: AUC: ↑ 4 % (↓ 3 to ↑ 11) Cmax: ↑ 3 % (↓ 3 to ↑ 9) Cmin: NC Emtricitabine: AUC: ↓ 5 % (↓ 9 to ↓ 1) Cmax: ↓ 11 % (↓ 17 to ↓ 5) Cmin: NC Tenofovir: AUC: ↑ 6 % (↓ 1 to ↑ 13) Cmax: ↑ 13 % (↑ 1 to ↑ 27) Cmin: NC |
No tacrolimus dose adjustment required. |
| NARCOTIC ANALGESICS |
||
| Methadone/tenofovir disoproxil fumarate |
Methadone: AUC: ↑ 5 % (↓ 2 to ↑ 13) Cmax: ↑ 5 % (↓ 3 to ↑ 14) Cmin: NC |
No methadone dose adjustment required. |
NC – not calculated.
N/A – not applicable.
1 Data obtained with concomitant administration with ledipasvir/sofosbuvir. Sequential administration (12 hours apart) yielded similar results.
2 Predominant circulating metabolite of sofosbuvir.
3 Study conducted with an additional dose of voxilaprevir 100 mg to achieve voxilaprevir exposure expected in patients infected with hepatitis C virus.
Special precautions for use.
HIV transmission
Since effective viral suppression with antiretroviral therapy using Emtricitabine/Tenofovir disoproxil fumarate has not been proven to substantially reduce the risk of sexual transmission of infection, residual risk cannot be excluded. Preventive measures to avoid transmission should be taken in accordance with national recommendations.
Patients with HIV-1 mutations
The use of this medicinal product should be avoided in antiretroviral-experienced patients infected with HIV-1 strains carrying the K65R mutation (see section "Pharmacodynamics").
HIV-infected patients with concomitant hepatitis B or C virus infection
HIV-infected patients with chronic hepatitis B or C undergoing antiretroviral therapy have an increased risk of severe and potentially fatal hepatic adverse reactions. Physicians should refer to current HIV treatment guidelines for managing HIV infection in patients with concomitant hepatitis B virus (HBV) and hepatitis C virus (HCV) co-infection.
When prescribing concomitant antiviral therapy for hepatitis B or C, reference should also be made to the relevant product information for these medicinal products (see section "Use with ledipasvir and sofosbuvir or sofosbuvir and velpatasvir").
Tenofovir disoproxil fumarate is indicated for the treatment of hepatitis B virus, and emtricitabine has demonstrated activity against hepatitis B virus in pharmacodynamic studies. However, the safety and efficacy of Emtricitabine/Tenofovir disoproxil fumarate for the treatment of patients with chronic HBV infection have not been established.
Discontinuation of Emtricitabine/Tenofovir disoproxil fumarate in patients co-infected with HIV and HBV may be associated with severe acute exacerbations of hepatitis. Patients co-infected with HIV and HBV who discontinue the medicinal product should be closely monitored both clinically and through laboratory testing for at least several months after stopping therapy. Resumption of hepatitis B treatment may be warranted if necessary. Discontinuation of therapy is not recommended in patients with advanced liver disease or cirrhosis, as hepatitis flare after treatment may lead to hepatic decompensation.
Liver disease
The safety and efficacy of the medicinal product in patients with pre-existing severe hepatic impairment have not been established. The pharmacokinetics of tenofovir have been studied in patients with hepatic impairment; therefore, no dose adjustment is required in these patients. The pharmacokinetics of emtricitabine in patients with hepatic impairment have not been studied. Given the minimal hepatic metabolism and renal elimination pathway of emtricitabine, it is unlikely that patients with hepatic impairment will require dose adjustment (see sections "Pharmacokinetics" and "Posology and method of administration").
HIV-infected patients with pre-existing hepatic dysfunction, including chronic active hepatitis, have an increased frequency of liver function abnormalities during combination antiretroviral therapy (cART), and they should be monitored according to standard clinical practice. If there is evidence of worsening liver disease, consideration should be given to interrupting or discontinuing therapy.
Renal and bone effects in adults
Renal effects
Emtricitabine and tenofovir are primarily eliminated by the kidneys through a combination of glomerular filtration and active tubular secretion. Cases of renal failure, renal impairment, increased creatinine levels, hypophosphatemia, and proximal tubulopathy (including Fanconi syndrome) have been reported with the use of tenofovir disoproxil fumarate (see section "Adverse reactions").
Renal monitoring
Prior to initiating HIV-1 infection treatment with this medicinal product, creatinine clearance should be determined in all patients. In patients without risk factors for kidney disease, renal function (creatinine clearance and serum phosphate levels) should be monitored 2–4 weeks after starting treatment and every 3–6 months thereafter. Patients at risk of kidney disease require more frequent monitoring of renal function.
See also "Concomitant use of other medicinal products" below.
Renal management in HIV-1-infected patients
If serum phosphate levels are < 1.5 mg/dL (0.48 mmol/L) or creatinine clearance decreases to < 50 mL/min in any patient taking the medicinal product, renal function should be re-evaluated within one week, including measurement of blood glucose and potassium concentrations and glucose in urine (see section "Adverse reactions"). The medicinal product should be discontinued in patients with creatinine clearance < 50 mL/min or reduced serum phosphate concentration to < 1.0 mg/dL (0.32 mmol/L). Discontinuation of the medicinal product should also be considered in cases of progressive renal function decline if no other cause is identified. The safety of the medicinal product without renal impact has been partially studied in HIV-1-infected patients with renal impairment (creatinine clearance < 80 mL/min). For HIV-1-infected patients with creatinine clearance of 30–49 mL/min, dose interval adjustment is recommended (see section "Posology and method of administration"). Limited clinical trial data suggest that prolonged dosing intervals are suboptimal and may lead to increased toxicity and possibly unknown resistance. Additionally, in a small clinical study of patients with creatinine clearance between 50 mL/min and 60 mL/min receiving tenofovir disoproxil fumarate in combination with emtricitabine every 24 hours, tenofovir levels were 2–4 times higher and renal function worsened (see section "Pharmacological properties"). Therefore, the benefit-risk ratio should be carefully evaluated and renal function closely monitored if the medicinal product is administered to patients with creatinine clearance < 60 mL/min. Furthermore, clinical response to therapy should be carefully monitored in patients receiving the medicinal product with prolonged dosing intervals. The use of the medicinal product is not recommended in patients with severe renal impairment (creatinine clearance < 30 mL/min) or in patients requiring hemodialysis, as the fixed-dose combination tablet does not allow for the necessary dose reduction (see sections "Pharmacological properties" and "Posology and method of administration").
Bone effects
Bone abnormalities, such as osteomalacia, which may manifest as persistent or worsening bone pain and sometimes lead to fractures, may be associated with tenofovir disoproxil-induced proximal renal tubulopathy (see section "Adverse reactions"). Tenofovir disoproxil fumarate may cause a decrease in BMD.
If bone abnormalities are suspected or identified, appropriate specialist consultations should be obtained.
HIV-1 infection treatment
In both treatment groups of a controlled clinical trial (GS-99-903) comparing tenofovir disoproxil fumarate with stavudine in combination with lamivudine and efavirenz in antiretroviral-naïve patients, a small decrease in BMD of the hip and spine was observed at week 144. The decrease in spine BMD and changes in bone biomarkers from baseline were significantly greater in the tenofovir disoproxil fumarate group over 144 weeks. The decrease in hip BMD was significantly greater in this group up to week 96. However, after 144 weeks, no increased risk of fractures or clinically significant bone abnormalities was observed in this study.
In other studies (prospective and cross-sectional), the most pronounced BMD decrease was observed in patients receiving tenofovir disoproxil fumarate as part of a regimen containing a boosted protease inhibitor. Overall, due to bone disorders associated with tenofovir disoproxil and limited data on the long-term impact of this drug on bone health and fracture risk, alternative treatment regimens should be considered for patients with osteoporosis who are at high risk of fractures.
Renal and bone effects in pediatric populations
There is uncertainty regarding the long-term impact of tenofovir disoproxil fumarate on bone health and renal toxicity. Additionally, the reversibility of renal toxicity cannot be fully determined. Therefore, a multidisciplinary approach is recommended for each individual case to assess the benefit-risk balance of treatment, determine appropriate monitoring during treatment (including decisions on discontinuation), and consider the need for additional measures.
Renal effects
Cases of adverse reactions in the form of proximal renal tubulopathy have been reported in HIV-1-infected pediatric patients aged 2 to 12 years in clinical trial GS-US-104-0352 (see sections "Pharmacodynamics" and "Adverse reactions").
Renal monitoring
Renal function (creatinine clearance and serum phosphate levels) should be assessed prior to initiating treatment and monitored during treatment in the same manner as in HIV-1-infected adults (see above).
Renal function monitoring
If serum phosphate levels are < 3.0 mg/dL (0.96 mmol/L) in any pediatric patient receiving the medicinal product, renal function should be re-evaluated within one week, including measurement of blood glucose and potassium concentrations and glucose in urine (see section "Adverse reactions", proximal tubulopathy). If renal abnormality is suspected or identified, consultation with a nephrologist should be sought to consider discontinuation of treatment. Discontinuation of treatment should also be considered in cases of progressive renal function decline if no other cause is identified.
Concomitant use of other medicinal products and risk of renal toxicity
The same recommendations apply as for adults (see section "Concomitant use of other medicinal products" below).
Renal impairment
The use of this medicinal product is not recommended in patients under 18 years of age with renal impairment (see section "Posology and method of administration"). The use of Emtricitabine/Tenofovir disoproxil fumarate should not be initiated in pediatric patients with renal impairment, and it should be discontinued in pediatric patients who develop renal impairment during treatment with Emtricitabine/Tenofovir disoproxil fumarate.
Bone effects
Tenofovir disoproxil fumarate may cause a decrease in BMD. The long-term consequences of BMD changes associated with tenofovir disoproxil fumarate on bone health and fracture risk have not yet been determined (see section "Pharmacodynamics"). If bone abnormalities are identified or suspected in pediatric patients, consultation with an endocrinologist and/or nephrologist is necessary.
Body weight and metabolic parameters
During antiretroviral therapy, increases in body weight and elevations in serum lipid and glucose levels may occur. These changes may be partly related to therapy and lifestyle. In some cases, treatment may affect lipid levels, but there is no substantial evidence linking increased body weight to any specific medicinal product. Current HIV treatment guidelines recommend monitoring of blood lipid and glucose levels. If clinically indicated, lipid abnormalities should be treated.
Mitochondrial dysfunction due to in utero exposure
Nucleoside and nucleotide analogues may significantly affect mitochondrial function, particularly stavudine, didanosine, and zidovudine. Cases of mitochondrial dysfunction have been reported in HIV-negative children exposed in utero and/or postnatally to nucleoside analogues, primarily in regimens containing zidovudine. The main adverse events reported were hematological disorders (anemia, neutropenia) and metabolic disorders (hyperlactatemia, hyperlipasemia). These events are often transient. Rarely, delayed-onset neurological disorders (hypertension, seizures, abnormal behavior) have been reported. It is currently unknown whether these neurological disorders are transient or permanent. These findings should be considered in any child exposed in utero to nucleoside or nucleotide analogues who presents with a clinical condition of unknown etiology, particularly neurological findings. These findings do not affect current national recommendations for the use of antiretroviral therapy in pregnant women to prevent vertical transmission of HIV.
Immune reconstitution syndrome
In HIV-infected patients with severe immune deficiency at the time of initiation of cART, an inflammatory reaction to asymptomatic or residual opportunistic pathogens may occur, potentially causing serious clinical conditions or symptom exacerbation. Such reactions are typically observed within the first few weeks or months of cART. Examples include cytomegalovirus retinitis, generalized and/or localized mycobacterial infections, and Pneumocystis jirovecii pneumonia. Any inflammatory symptoms should be evaluated and treated if necessary.
Autoimmune disorders (such as Graves' disease and autoimmune hepatitis) have also been reported during immune reconstitution; however, the time to onset varied widely, and these events may occur many months after starting treatment.
Opportunistic infections
HIV-1-infected patients receiving Emtricitabine/Tenofovir disoproxil fumarate or any other antiretroviral therapy may still develop opportunistic infections and other complications of HIV infection and should remain under continuous clinical monitoring by physicians experienced in managing HIV-1-infected patients.
Osteonecrosis
Although the etiology is considered multifactorial (including corticosteroid use, alcohol consumption, severe immunosuppression, high body mass index), cases of osteonecrosis have been observed, particularly in patients with advanced HIV disease and/or long-term cART. Patients should be advised to seek medical attention if they experience joint pain, stiffness, or difficulty moving.
Concomitant use of other medicinal products
The use of Emtricitabine/Tenofovir disoproxil fumarate should be avoided with concomitant or recent use of nephrotoxic medicinal products (see section "Interaction with other medicinal products and other forms of interaction"). If concomitant use of Emtricitabine/Tenofovir disoproxil fumarate and nephrotoxic agents cannot be avoided, renal function should be monitored weekly.
Cases of acute renal failure have been reported in HIV-1-infected patients receiving tenofovir disoproxil fumarate who initiated high-dose or multiple nonsteroidal anti-inflammatory drugs (NSAIDs). If the medicinal product is used with NSAIDs, renal function should be closely monitored.
An increased risk of renal dysfunction has been observed in HIV-1-infected patients receiving tenofovir disoproxil fumarate in combination with a ritonavir- or cobicistat-boosted protease inhibitor. These patients require close monitoring of renal function (see section "Interaction with other medicinal products and other forms of interaction"). For HIV-1-infected patients with risk factors for kidney disease, concomitant use of tenofovir disoproxil fumarate with a boosted protease inhibitor should be carefully evaluated.
Emtricitabine/Tenofovir disoproxil fumarate should not be co-administered with other medicinal products containing emtricitabine, tenofovir disoproxil (as fumarate), tenofovir alafenamide, or other cytidine analogues such as lamivudine (see section "Interaction with other medicinal products and other forms of interaction"). The medicinal product should not be used concomitantly with adefovir dipivoxil.
Use with ledipasvir and sofosbuvir, sofosbuvir and velpatasvir, or sofosbuvir, velpatasvir and voxilaprevir
Concomitant use of tenofovir disoproxil fumarate with ledipasvir/sofosbuvir, sofosbuvir/velpatasvir, or sofosbuvir/velpatasvir/voxilaprevir has been shown to increase tenofovir plasma concentrations, particularly when used with an HIV regimen containing tenofovir disoproxil fumarate and a pharmacokinetic booster (ritonavir or cobicistat).
The safety of tenofovir disoproxil fumarate with concomitant use of ledipasvir/sofosbuvir, sofosbuvir/velpatasvir, or sofosbuvir/velpatasvir/voxilaprevir and a pharmacokinetic booster has not been established. The potential risks and benefits of concomitant use should be carefully considered, especially in patients at increased risk of renal dysfunction. In patients receiving ledipasvir/sofosbuvir, sofosbuvir/velpatasvir, or sofosbuvir/velpatasvir/voxilaprevir concomitantly with tenofovir disoproxil fumarate and a boosted HIV protease inhibitor, adverse reactions associated with tenofovir disoproxil fumarate should be monitored.
Concomitant use of tenofovir disoproxil fumarate and didanosine
Concomitant use of tenofovir disoproxil and didanosine is not recommended (see section "Interaction with other medicinal products and other forms of interaction").
Nucleoside triple therapy
Reports of high rates of virological failure and early emergence of resistance have been reported in HIV-1-infected patients when tenofovir disoproxil fumarate was combined with lamivudine and abacavir, as well as with lamivudine and didanosine once daily. There is close structural similarity between lamivudine and emtricitabine and similarity in the pharmacokinetics and pharmacodynamics of these two drugs. Therefore, similar issues may arise if the medicinal product is used with a third nucleoside analogue.
Elderly patients
The effect of the medicinal product has not been studied in individuals aged 65 years and older. Elderly individuals often have reduced renal function; therefore, caution should be exercised when administering the medicinal product to these patients.
Excipients
Emtricitabine/Tenofovir disoproxil fumarate contains lactose monohydrate. Patients with rare hereditary problems such as galactose intolerance, total lactase deficiency, or glucose-galactose malabsorption should not take this medicinal product.
This medicinal product contains less than 1 mmol (23 mg) of sodium per tablet, i.e., essentially "sodium-free."
Use during pregnancy or breastfeeding.
Pregnancy
Extensive data from pregnancy (over 1000 completed pregnancies) indicate no malformations or embryonic/neonatal toxicity associated with emtricitabine and tenofovir disoproxil. Animal studies with emtricitabine and tenofovir disoproxil did not show reproductive toxicity. Therefore, the use of this medicinal product during pregnancy is possible if necessary.
Breastfeeding
Emtricitabine and tenofovir have been detected in human breast milk. There is insufficient information on the effects of emtricitabine and tenofovir on newborns/infants. Therefore, Emtricitabine/Tenofovir disoproxil fumarate should not be used during breastfeeding.
HIV-infected women should not breastfeed under any circumstances to avoid transmission of HIV to the infant.
Fertility
There are no data on the effect of the medicinal product on humans. Animal studies do not indicate harmful effects of emtricitabine and tenofovir disoproxil fumarate on fertility.
Ability to drive and use machines.
Studies on the effect on the ability to drive and operate machinery have not been conducted. However, patients should be informed that dizziness may occur during treatment with both emtricitabine and tenofovir disoproxil fumarate.
Dosage and Administration
The medicinal product should be prescribed by a physician experienced in the management of HIV infection.
Dosage
Treatment of HIV infection in adults and adolescents aged 12 years and older with body weight ≥ 35 kg: One tablet once daily.
Separate emtricitabine and tenofovir disoproxil fumarate medicinal products are available for the treatment of HIV-1 infection, which may be used if there is a need to discontinue or adjust the dose of one of the components of this medicinal product (see the “Summary of Product Characteristics” for these medicinal products).
If less than 12 hours have passed since the missed dose, the dose should be taken as soon as possible, and the regular dosing schedule should be resumed. If more than 12 hours have passed since the last dose and the next scheduled dose is approaching, the missed dose should not be taken; instead, resume the regular dosing schedule.
If vomiting occurs within 1 hour after taking the medicinal product, another tablet should be taken. If vomiting occurs more than 1 hour after administration, an additional dose is not required.
Special patient populations
Elderly patients. No dose adjustment is necessary (see section “Pharmacokinetics”).
Renal impairment. Emtricitabine and tenofovir are eliminated renally; therefore, the effects of emtricitabine and tenofovir are increased in patients with impaired renal function (see sections “Pharmacokinetics” and “Special warnings and precautions for use”).
Adults with renal impairment. This medicinal product may be used in patients with CrCl < 80 mL/min only if the anticipated benefit outweighs the potential risk (see Table 2).
Table 2
Dosage recommendations for adult patients with renal impairment
| Treatment of HIV-1 infection |
|
| Mild renal impairment (CrCl 50–80 mL/min) |
Limited data from clinical studies support administration of Emtricitabine/Tenofovir disoproxil fumarate once daily (see section "Special instructions for use"). |
| Moderate renal impairment (CrCl 30–49 mL/min) |
Administration of the medicinal product every 48 hours is recommended, based on pharmacokinetic modeling of single-dose data for emtricitabine and tenofovir disoproxil fumarate in HIV-uninfected individuals with varying degrees of renal impairment (see section "Special instructions for use"). |
| Acute renal failure (CrCl < 30 mL/min) and patients on hemodialysis |
Use of the medicinal product is not recommended, as appropriate dose reduction cannot be achieved with combination medicinal products. |
Pediatric patients with renal impairment. The use of emtricitabine/tenofovir disoproxil fumarate is not recommended in patients under 18 years of age with impaired renal function (see section "Special instructions").
Hepatic impairment. Dose adjustment is not required for patients with hepatic impairment (see sections "Pharmacokinetics" and "Special instructions").
Children. Safety and efficacy of the medicinal product in children under 12 years of age have not been established (see section "Pharmacokinetics").
Method of administration
Oral administration. Emtricitabine/tenofovir disoproxil fumarate tablets should be taken with food.
Emtricitabine/tenofovir disoproxil fumarate tablets may be crushed and dispersed in approximately 100 mL of water, orange juice, or grape juice and administered immediately.
Children.
Safety and efficacy of the medicinal product in children under 12 years of age have not been established (see section "Pharmacokinetics").
Overdose.
In case of overdose, patients should be monitored for signs of toxicity (see section "Adverse reactions"); if necessary, standard supportive treatment should be administered.
Up to 30% of the emtricitabine dose and approximately 10% of the tenofovir dose may be removed by hemodialysis. It is not known whether emtricitabine or tenofovir is removed by peritoneal dialysis.
Adverse Reactions
Safety Profile
In an open-label randomized clinical study in adults (GS-01-934, see section "Pharmacodynamics"), the most common adverse reactions considered possibly related to emtricitabine and/or tenofovir disoproxil fumarate were nausea (12%) and diarrhea (7%). The safety profile of emtricitabine and tenofovir disoproxil fumarate in this study was consistent with the previous experience of using each of these agents separately with other antiretroviral drugs.
Summary Table of Adverse Reactions
Adverse reactions possibly related to the components of the medicinal product observed in clinical trials and post-marketing use in HIV-1-infected patients are listed in Table 3 by system organ classes and frequency. Within each frequency group, adverse reactions are presented in descending order of severity. Frequency is defined as: very common (≥ 1/10), common (≥ 1/100 to < 1/10), uncommon (≥ 1/1000 to < 1/100), or rare (≥ 1/10,000 to < 1/1000).
Table 3
Adverse reactions associated with individual components of the medicinal product based on clinical trial and post-marketing experience
| Frequency |
Emtricitabine |
Tenofovir disoproxil fumarate |
| Blood and lymphatic system disorders |
||
| Common |
neutropenia |
|
| Uncommon |
anemia2 |
|
| Immune system disorders |
||
| Common |
allergic reactions |
|
| Metabolism and nutrition disorders |
||
| Very common |
hypophosphatemia1 |
|
| Common |
hyperglycemia, hypertriglyceridemia |
|
| Uncommon |
hypokalemia1 |
|
| Rare |
lactic acidosis |
|
| Psychiatric disorders |
||
| Common |
insomnia, abnormal dreams |
|
| Nervous system disorders |
||
| Very common |
headache |
dizziness |
| Common |
dizziness |
headache |
| Gastrointestinal disorders |
||
| Very common |
diarrhea, nausea |
|
| Common |
increased amylase levels, including increased pancreatic amylase, increased serum lipase levels, vomiting, abdominal pain, dyspepsia |
abdominal pain, abdominal distension, flatulence |
| Uncommon |
pancreatitis |
|
| Hepatobiliary disorders |
||
| Common |
increased serum aspartate aminotransferase (AST) and/or increased serum alanine aminotransferase (ALT), hyperbilirubinemia |
increased transaminases |
| Rare |
fatty liver degeneration, hepatitis |
|
| Skin and subcutaneous tissue disorders |
||
| Very common |
Rash |
|
| Common |
vesiculobullous rash, pustular rash, maculopapular rash, rash, pruritus, urticaria, skin color changes (increased pigmentation)2 |
|
| Uncommon |
angioneurotic edema3 |
|
| Rare |
angioneurotic edema |
|
| Musculoskeletal and connective tissue disorders |
||
| Very common |
increased creatine kinase |
|
| Uncommon |
acute skeletal muscle necrosis1,3, muscle weakness1 |
|
| Rare |
osteomalacia (manifested as bone pain and infrequently contributing to fractures)1,3, myopathy1 |
|
| Renal and urinary disorders |
||
| Uncommon |
increased creatinine, proteinuria, proximal renal tubulopathy, including Fanconi syndrome |
|
| Rare |
renal failure (acute and chronic), acute tubular necrosis, nephritis (including acute interstitial nephritis)3, nephrogenic diabetes insipidus |
|
| General disorders and administration site conditions |
||
| Very common |
asthenia |
|
| Common |
pain, asthenia |
|
1 A side effect may occur as a result of proximal renal tubulopathy. It is not considered to be causally associated with tenofovir disoproxil fumarate in the absence of this condition.
2 Anemia was common, skin discoloration (increased pigmentation) was very common when emtricitabine was used in pediatric patients.
3 This adverse reaction was identified during post-marketing surveillance but was not observed in randomized controlled clinical trials in adults or clinical trials of emtricitabine for HIV treatment in children, or in randomized controlled clinical trials or expanded access programs of tenofovir disoproxil fumarate. The frequency category was established based on statistical calculations using the total number of patients who received emtricitabine in randomized controlled clinical trials and expanded access programs (n = 1,563) or tenofovir disoproxil fumarate in randomized controlled clinical trials and expanded access programs (n = 7,319).
Description of selected adverse reactions
Renal failure. Since the medicinal product Emtricitabine/Tenofovir disoproxil fumarate may lead to impaired kidney function, monitoring of renal function is recommended (see section "Special precautions"). Proximal renal tubulopathy generally resolved or improved after discontinuation of tenofovir disoproxil fumarate. However, in some HIV-infected patients, reduced creatinine clearance did not completely resolve despite discontinuation of tenofovir disoproxil fumarate. Patients at risk of renal function impairment (e.g., patients with baseline risk factors for renal dysfunction, patients with advanced HIV disease, or patients receiving concomitant therapy with nephrotoxic agents) have an increased risk of incomplete recovery of renal function despite discontinuation of tenofovir disoproxil fumarate (see section "Special precautions").
Lactic acidosis. Cases of lactic acidosis have been reported during treatment with tenofovir disoproxil alone or in combination with other antiretroviral agents. Patients with predisposing conditions, namely those with decompensated liver disease or those receiving concomitant medications that can cause lactic acidosis, have an increased risk of developing severe lactic acidosis during treatment with tenofovir disoproxil, sometimes with fatal outcome.
Metabolic parameters. During antiretroviral therapy, a patient's body weight as well as blood lipid and glucose levels may increase (see section "Special precautions").
Immune Reconstitution Syndrome. In HIV-infected patients with severe immunodeficiency at the time of initiation of combination antiretroviral therapy, an inflammatory response to asymptomatic or residual opportunistic pathogens may occur. Autoimmune disorders (such as Graves' disease and autoimmune hepatitis) have also been reported; however, the reported time to onset of disease varied widely and these events may occur many months after initiation of treatment (see section "Special precautions").
Osteonecrosis. Cases of osteonecrosis have been observed in patients with risk factors, advanced HIV disease, or with long-term use of combination antiretroviral therapy. The frequency of this event is unknown (see section "Special precautions").
Elderly patients. The use of the medicinal product in elderly patients has not been studied. Elderly patients are more likely to have decreased renal function; therefore, caution should be exercised when administering the medicinal product to elderly patients (see section "Special precautions").
Pediatric patients
The assessment of adverse reactions related to emtricitabine is based on three pediatric studies (n = 169), in which HIV-infected patients aged from 4 months to 18 years received emtricitabine in combination with other antiretroviral agents: treatment-naïve patients (n = 123) and treatment-experienced patients (n = 46). In addition to adverse reactions reported in adults, anemia (9.5%) and skin discoloration (31.8%) occurred more frequently in clinical trials in children than in adults (see section "Adverse reactions", Summary table of adverse reactions).
The assessment of adverse reactions related to tenofovir disoproxil fumarate is based on two randomized studies (studies GS-US-104-0321 and GS-US-104-0352), in which 184 HIV-1-infected pediatric patients (aged 2 to 18 years) received tenofovir disoproxil fumarate (n = 93) or placebo/active comparator (n = 91) in combination with other antiretroviral agents. Treatment lasted for 48 weeks (see section "Pharmacodynamics"). Adverse reactions in pediatric patients receiving tenofovir disoproxil fumarate were consistent with those observed in clinical trials of tenofovir disoproxil fumarate in adults (see sections "Pharmacodynamics" and "Adverse reactions", Summary table of adverse reactions).
In pediatric patients, decreased bone mineral density has been reported. In HIV-1-infected adolescents (aged 12 to 18 years), Z-scores of BMD were lower with tenofovir disoproxil fumarate than with placebo. In HIV-1-infected children (aged 2 to 15 years), Z-scores of BMD recorded after switching to tenofovir disoproxil fumarate were lower than with continuation of regimens containing stavudine or zidovudine (see sections "Pharmacodynamics" and "Special precautions").
In study GS-US-104-0352, 89 pediatric patients with a mean age of 7 years (aged 2 to 15 years) received tenofovir disoproxil fumarate for a median duration of 331 weeks. Eight of 89 patients (9.0%) discontinued clinical trials of the medicinal product due to renal adverse events. Clinical laboratory assessments for proximal renal tubulopathy were performed in five patients (5.6%), four of whom discontinued tenofovir disoproxil fumarate treatment. Glomerular filtration rate (GFR) was measured in seven patients and ranged from 70 to 90 mL/min/1.73 m². Of these, three patients experienced clinically significant decreases in GFR during therapy, which improved after discontinuation of tenofovir disoproxil fumarate.
Other special patient groups
Patients with renal impairment. Since tenofovir disoproxil fumarate may lead to nephrotoxicity, careful monitoring of renal function is recommended in all adults with renal impairment receiving the medicinal product (see sections "Pharmacokinetics", "Special precautions", and "Dosage and administration"). The use of this medicinal product is not recommended in pediatric patients with renal impairment (see sections "Special precautions" and "Dosage and administration").
Patients with concomitant HIV/hepatitis B virus or hepatitis C virus infections. The adverse reaction profile of emtricitabine and tenofovir disoproxil fumarate in a limited number of HIV-infected patients co-infected with hepatitis B virus (n = 13) or hepatitis C virus (n = 26) in study GS-01-934 was similar to that observed in HIV-infected patients without concomitant infection. However, as expected in this patient population, elevations in aspartate aminotransferase (AST) and alanine aminotransferase (ALT) were observed more frequently than in the general HIV-infected population.
Hepatitis flare after discontinuation of treatment. Clinical and laboratory signs of hepatitis flare have occurred in patients infected with hepatitis B virus after discontinuation of treatment (see section "Special precautions").
Reporting suspected adverse reactions after authorization of the medicinal product is important. It allows continued monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals and patients are encouraged to report any suspected adverse reactions and lack of efficacy via the Automated Pharmacovigilance Information System at the following link: https://aisf.dec.gov.ua.
Shelf life.
3 years.
Storage conditions.
Store at temperatures not exceeding 30 °C in the original packaging.
Keep out of the reach of children.
Packaging.
30 tablets in a bottle with desiccant, 1 bottle in a cardboard box.
Prescription status.
Prescription only.
Manufacturer.
Mylan Laboratories Limited
Mylan Laboratories Limited
Manufacturer's address and location of operations.
Plot No. 11, 12 & 13, Indore Special Economic Zone, Pharma Zone, Phase-II, Sector-III, Pithampur, District Dhar, Madhya Pradesh, 454775, India
or
H-12 & H-13, MIDC, Waluj, Aurangabad, Maharashtra State, 431136, India
Marketing Authorization Holder.
M.BIOTECH LIMITED
M.BIOTECH LIMITED
Address of the Marketing Authorization Holder.
Gladstone House, 77-79 High Street, Egham TW20 9HY, Surrey, United Kingdom